This invention relates to the use of an in vivo electrochemical method to measure the amounts of biogenic chemicals present in the body and brain of an animal or a human being. More particularly, it relates to the use of in vivo semiderivative voltammetric measurements of biogenic chemicals, particularly neurotransmitters, such as amines, amine metabolites, ascorbic acid, amino acids and neuropeptides produced in reaction to psychopharmacological agents and neuropsychopharmacological agents such as analgesics, antipsychotic drugs, anti-depressants, and other modulators of brain and peripheral neurochemistry in diseased and healthy states.
It has been known to those possessing ordinary skill in the art that it is possible to measure certain limited types chemicals using in vivo electrochemistry in the brains and suborgans of nonhuman primates and other animals. This measurement has been accomplished using such facets of electrochemical measurements as chronoamperometry, differential pulse voltammetry, double differential pulse voltammetry, linear scan voltammetry, and semiderivative voltammetry. In all of these methods, a working electrode, a reference electrode and an auxiliary electrode are attached to the brain or other organ of the animal to be studied. A controlled potential is applied to the working electrode and the current passing between the working electrode and the reference electrode is monitored as a signal and used to measure basal neurotransmitter release and any alterations in brain neurochemistry. The signal is directly related to the chemical concentration of the neurotransmitter released from the neuronal brain membrane presynaptically, or possibly postsynaptically and represents an instantaneous readout of rate of neuronal mechanism. The signal may also be related to inhibition of normal reuptake of neurotransmitter at the neuronal membrane and may be a summation of release and reuptake processes, especially during treatment. The prior art teaches that this current is an anodic (oxidation) current, based on scientific principle. This signal is recorded as a graph indicating change in current with respect to time (chronoamperogram) or voltage (voltammogram).
It is known that voltammetric measurements can be used to detect certain biogenic substances in the brain of rats [Kissinger, P. T.; Hart, J. B.; Adams, R. N.; "Voltammetry in Brain Tissue - A New Neurophysiological Measurement", Brain Research, 55 (1973), p. 209.]. Other researchers have also detected signals in the brains of living rats, as follows: McCreery, et al., Brain Res. Vol. 73 (1974), p. 23; Gonon, et al , Brain Res. Vol. 223 (1981), p. 69; Lane, et al., J. Electroanal. Chem., Vol. 95 (1979), p. 117; Clemens and Phebus, Brain Res., Vol. 267 (1983), p. 183 and Millar, et al., Eur. Pharmacol. Vol. 109 (1985), p. 341.
There has been, however, little or no description of circuitry for in vivo electrochemical circuits even though certain improvements have been made in voltammetric measurements since the linear scan for in vivo electrochemistry method was first described for measuring biogenic chemicals. One such improvement was the in vitro processing of the linear scan current signal as the first half-derivative of the linear signal [Oldham, "Analytical Chemistry" Vol. 45 (1973) p. 39 and U.S. Pat. No. 3,868,578; Kanazawa, U.S. Pat. No. 4,449,552]. However, neither Oldham nor Kanazawa describe circuitry applicable for detection of organic materials in living organisms. Although they describe oxidation and reduction reaction species, they do not describe cathodic (reduction) currents. For the purposes of this application, cathodic current is defined as current based on the acquisition of electrons by neurochemicals within the organ or suborgan and flowing away from an indicator electrode situated within the organ or suborgan. Anodic current is defined as current based on the loss of electrons by neurochemicals in the organ or suborgan and flowing toward an indicator electrode situated within the organ or suborgan.
When applied to the brain, or other body organs, this type of processing should result in a semidifferentiated voltammogram having sharper peaks, which then allows greater separation between peaks representing chemical substances and which are easier to read than previous, linear voltammograms. Older conventional methods did not allow individual detection of amines because similar electrochemical potentials, accompanying many of the biogenic amines and other chemicals, are set by the catechol moiety and not by the alkyl moiety of the biogenic amine and thus did not allow for separation of peaks between different amines, all of which contain the catechol moiety. Semiderivation or semidifferentiation of the signal briefly allowed somewhat better detection. Many practitioners, however, have found it difficult or impossible to obtain reproducible measurements routinely using what is known as the in vivo electrochemistry technique of semiderivative or semidifferential voltammetry.
Although telemetric devices have been produced in the past, as described in U.S. Pat. No. 4,424,812 (Lesnick) and U.S. Pat. No. 3,882,277 (DePedro), telemetric devices for monitoring brain signals have not been described. Neither of these patents describe monitoring signals produced electrochemically either in vivo, in vitro or in situ.
The wisdom of the prior art indicates that an oxidation current, or anodic current, should be used to detect biochemical species in the brain. Previous researchers assumed that in living systems, all chemical species which could be detected by electrochemical signals were converted into stable oxidized species. Most of the previous researchers also assumed that all biogenic chemical reactions produced oxidized species without producing stable reduced species. These assumptions have provided only a limited tool for diagnosing the mental and physiological states of living organisms, as only a limited number of biogenic chemicals can be detected using prior art methods.
Accordingly, it is an object of this invention to provide a method for measuring biogenic chemicals.
It is a further object of this invention to provide an in vivo electrochemical method for measuring biogenic chemicals.
It is still a further object to provide a useful way to measure biogenic chemicals using the semiderivative or semidifferential voltammetric technique to produce a cathodic current.
It is a further object of this invention to provide the circuitry for such a cathodic current.
It is still a further object of this invention to provide a cyclic voltammogram within the context of the cathodic current.
It is a further object of this invention to provide an in vivo electrochemical method for measuring biogenic amines, amine metabolites, ascorbic acid, amino acids and neuropeptides and other neurotransmitters and modulators of brain neurochemistry.
It is still a further object of this invention to provide an in vivo electrochemical method for measuring alterations in biogenic brain chemicals in relation to the administration, both peripheral and central, of psychopharmacological agents and neuropsychopharmacological agents such antidepressants, analgesics, antianxiety agents, anti-panic agents, anti-manic/depressive agents, calcium blocking agents, agents of addiction, other neuropeptides, enkephalinamides, dynorphin and other potential modulators of brain neurochemistry.
It is another object to provide an in vivo electrochemical method for interpreting these alterations in brain neurochemistry in light of diagnosing mental illness, Alzheimer's disease, and other diseased states, vis-a-vis healthy states, and developing new and more effective psychotherapeutic agents and other clinical applications.
It is a further object of this invention to provide an in vivo electrochemical method for measuring the levels and dynamic changes of biogenic chemicals with an instantaneous readout of rate in humans, in vivo.
It is still a further object of this invention to provide a means for studying the dynamic levels and/or release of biogenic chemicals produced during certain behavioral manifestations and thus provide a method for determining the causes of these manifestations.
It is another object of this invention to provide a method by which to correlate the production of certain biogenic chemicals with electrophysiological measurements.
Another object of this invention is the development of electrodes which are extremely selective to biogenic chemicals, which could be and are biological markers, and to describe the modification of such by biological brain and body fluids.
It is still a further object of this invention to provide a detailed description of reference, indicator (working) and auxiliary electrodes for the purpose of teaching the art of electrode fabrication.
An additional object of this invention is to provide a means for diagnosing illness in vivo, as opposed to the current manner of diagnosing illness from markers, i.e. post-mortem, from frozen brains and body organs.
Another object of this invention is to provide a telemetric method of diagnosing dynamic release mechanisms of biogenic chemicals such that a human patient may be continuously monitored without the impediment of wires.
Still another object of this invention is to describe peaks representing biogenic chemicals and neurotransmitters which have heretofore not been described and which influence behavior.
Still a further object of this invention is to provide a means for automating the in vivo monitoring of an animal or patient.
Yet another object of this invention is to provide neurochemical profiles from different brain regions, providing a neurochemical mapping device for diagnosis.